Our major objective will be to continue an analysis of drug actions on regional myocardial blood flow in different models of ischemia. In previous work, we carefully examined the effect of certain vasodilators and beta receptor antagonists on regional myocardial perfusion in models with partial or total main vessel coronary artery occlusion. We have recently extended these studies to include various slow channel calcium blocking agents. The radioactive microsphere technique has been the most precise measurement of regional blood flow but the results of drug intervention have been equivocal. A basic problem has been identified in the present studies which may resolve the confusion. an area of ischemic myocardium induced by coronary artery occlusion may receive overlap flow from another coronary artery and may receive true collateral blood flow creating peninsulas of normal tissue within the ischemic area. We are presently employing a special microsphere technique which can separate overlap and true collateral flow in an ischemic area. Preliminary studies suggest that different classes of drugs may affect overlap and collateral flow in different directions and by different mechanisms. The role of extravascular pressure and resistance in determining blood flow to ischemic myocardium has not been adequately analyzed. Underperfusion of the subendocardium is the major factor in the extent of ischemic damage in classical angina pectoris. Left ventricular systolic and end diastolic cavity pressures have long been recognized as being important factors in determining blood flow to the inner or subendocardial layers of the ventricular wall. Recent advances in technology have resulted in the development of miniature pressure transducers which can be inserted into the subepicardium and subendocardium of the ischemic area. Preliminary studies from our laboratory indicate that subendocardial systolic and diastolic pressures are significantly different from corresponding subepicardial or left ventricullar cavity pressures. It appears that some drugs increased collateral blood flow by decreasing extravascular pressure within the ischemic bed. The new technology permits us to measure tissue pressures and local contractility (dp/dt) in an attempt to elucidate mechanisms by which drugs affect ischemic area perfusion. We will also gain a better understanding of the physiological factors that regulate regional blood flow in the ischemic heart.